The sensory hair cells of the inner ear are necessary for the detection of sound and head movement. Hair cells may be lost from the inner ear as a result of noise exposure, treatment with certain drugs, or as a consequence of aging. Recent evidence has shown that hair cells can regenerate in the ears of adult birds and mammals, and that supporting cells in organ cultures of ears taken from adult humans will proliferate after the death of hair cells. These findings strongly suggest that hair cell regeneration may be induced in the ears of humans. In order to develop clinical strategies that will bring about hair cell regeneration in the human ear, it is first necessary to understand how regeneration is initiated. More specifically, we must know what cellular and molecular signals are responsible for triggering the regenerative proliferation of inner ear supporting cells after the death of hair cells, and how these cells then go on to form replacement hair cells. The goal of the proposed research is to identify factors that trigger regenerative proliferation in the ears of warm-blooded vertebrates. Experiments will be carried out that test the ability of identified mitogenic growth factors to enhance the regenerative proliferation of supporting cells in organ culture preparations of inner ear sensory epithelia taken from birds and from adult humans. Additional experiments will determine whether the vestibular sensory organs of adult birds produce a diffusible mitogenic growth factor. The role of leukocytes in the process of hair cell regeneration will also be explored. Finally, experiments will be conducted that will determine whether hair cells can also regenerate by differentiating from existing supporting cells, without any accompanying cell division.